Chronic pain can result from various disease conditions and about 45% of the U. S. population seeks medical help for treatment of pain. Neuropathic pain is a type of chronic pain which is very difficult to treat, and most patients do not get adequate relief. A promising therapeutic drug target for the treatment of inflammation and pain is the cannabinoid CB2 receptor. In Phase I of this proposal our focus will be on the structural optimization of our lead template to develop a high efficacy CB2 selective agonist with pain suppression potential and with no CNS side effects. Established in vivo and in vitro pharmacological assays will be used to identify compounds that: 1) are highly selective for CB2 over CB1 receptors; 2) possess high efficacy and high potency in binding and activating the CB2 receptor; 3) possess high efficacy in reversing allodynia (i.e., nociceptive behavior in response to normally non-noxious stimuli); and 4) lack cannabimimetic side effects in whole animals that are typically indicative of CB1 receptor activation. The long-term objective of this proposal is to develop a novel drug for treatment of chronic pain which is both safe and effective.